Mechanisms of IFN-alpha induced biologic response, signaling, cellular context, drug synergism and clinical biomarkers in myeloproliferative neoplasms

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Myeloproliferative neoplasms (MPN) are a heterogeneous group of human malignancies, including chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). They represent important model diseases for multistep carcinogenesis and cancer progression, and significant progress has been made in the treatment of MPN using targeted therapies, including tyrosine kinase inhibitors (TKI). On the other hand, interferon-alpha (IFNa) is successfully used for MPN therapy. It is clear from clinical experience that single agent IFNa is more potent against PV and ET than against PMF and CML, but the mechanisms are still poorly understood. In PV and ET, IFN is able to induce long-lasting molecular remissions, and some patients continue to sustain their molecular response even after discontinuation of IFN. However, the presence of additional mutations besides the so-called disease-driving mutations (i.e. JAK2V617F, CALR, MPL) has been described to be associated with clonal evolution during IFN treatment and failure to achieve a complete molecular remission (CMR). In addition, patients in CMR (no JAK2V617F mutation detected by Sanger sequencing) continued to harbor endogenous erythroid colonies (EECs), suggesting that immature cells may persist during CMR (which has been described for persistent CML stem cells despite molecular remissions) or that the EECs grow JAK2V617F-independently. Moreover, while beneficial for many patients with PV and ET, IFN therapy can induce significant adverse events, including autoimmune diseases and severe psychiatric disorders such as major depression, and these adverse events are difficult to predict in an individual patient. Therefore, in order to better understand the mechanisms of action of IFN in MPN and to help select patients that will benefit most from IFN treatment, the present proposal aims to (1) elucidate basic mechanisms of IFN treatment in MPN and define the causes for non-response in patients failing to achieve CMR, and (2) assess biomarkers for IFNa response and adverse events in patients with MPN. An improved understanding of these factors of IFN therapy will lead to a better selection of potentially suitable patients and deeper clinical responses in MPN and will identify patients that are in need for more aggressive or alternative treatment approaches.